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Cell Rep. 2017 Jun 13;19(11):2319-2330. doi: 10.1016/j.celrep.2017.05.058.

Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.

Author information

1
Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Mouse Pathology Platform, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, the Netherlands.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.
6
Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany. Electronic address: till.strowig@helmholtz-hzi.de.

Abstract

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1-/- and Casp11-/- mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1-/- mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.

KEYWORDS:

DSS; caspase-1; caspase-11; colitis; colon; inflammasome; inflammation-induced tumorigenesis; intestine; microbiota

PMID:
28614717
DOI:
10.1016/j.celrep.2017.05.058
[Indexed for MEDLINE]
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